LZTS1 (leucine zipper, putative tumor suppressor 1)

2012-06-01   Andrea Vecchione , Luca Lavra , Carlo M Croce 





NC_000008.10: 20103676 - 20112803 bp (Entrez-Gene).
Atlas Image
Genomic structure of the human LZTS1 gene.


According to Entrez-Gene, LZTS1 gene extends over 9 kb (9128 bases) and consists of 3 exons.


mRNA size: 5459 bp (NM_021020.2); open reading frame: 1791 bp (NP_066300.1).
LZTS1 mRNA is highly expressed in testis, prostate, spleen, thymus, ovary and brain. It has been detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. LZTS1 gene is not expressed in primary tumors from breast and prostate and in different cancer cell lines (Ishii et al., 1999).


No LZTS1 pseudogenes have been reported.


Atlas Image
Schematic representation of LZTS1 protein. The leucine residues position of leucine-zipper motifs are indicated by the gray bars.


LZTS1 gene encodes a 596-aa protein of 67 kDa. The protein contains two leucine-zipper motifs, multiple potential phosphorylation sites for different kinases (e.g. PKA, CDC2 and PKC) and a domain with 32% identity to the DNA binding domain of the cAMP-responsive transcription factor Atf5. LZTS1 lacks the DNA recognition domain usually found in transcription factors carrying a leucine-zipper motive (Ishii et al., 1999; Ishii et al., 2001; Vecchione et al., 2007b).


LZTS1 is ubiquitously expressed in all normal human tissues. LZTS1 protein expression is lost or reduced in different primary tumors.


Main sub-cellular localizations: plasma membrane and cytoplasm.
Additional localizations: nucleoli (observed in U2-OS cells) and Golgi apparatus (observed in A-431 cells) (Barbe et al., 2008).


Cell cycle regulation. It has been demonstrated that Lzts1-/- mouse embryonic fibroblasts (MEF) have a faster M phase, associated with a lower cyclin B1/Cdk1 activity. During prophase the interaction between LZTS1 and Cdc25C, a phosphatase implicated in regulation of Cdk1 activity, allows the expression of high levels of Cdc25C and enhances its activity, resulting in normal progression from prophase to metaphase. In Lzts1 deficient cells during prophase Cdc25C is rapidly ubiquitinated and degraded, thus determining a lower activity of the cyclin B1/Cdk1 complex. This results in a faster cellular progression through prophase and prometaphase and, frequently, in chromosome missegregation (Vecchione et al., 2007b).


The LZTS1 gene is conserved in the organisms listed below:
- Pan troglodytes (LZTS1) (Gene ID: 464034)
- Macaca mulatta (LZTS1) (Gene ID: 705724)
- Mus musculus (Lzts1) (Gene ID: 211134)
- Rattus norvegicus (Lzts1) (Gene ID: 266711)
- Bos taurus (LZTS1) (Gene ID: 539634)
- Equus caballus (LZTS1) (Gene ID: 100053630)
- Canis lupus familiaris (LZTS1) (Gene ID: 486136)
- Monodelphis domestica (LZTS1) (Gene ID: 100030407)
- Ornithorhynchus anatinus (LZTS1) (Gene ID: 100073437)
- Gallus gallus (LZTS1) (Gene ID: 431331)
- Danio rerio (si:dkey-63d15.13) (Gene ID: 569281).



Sequence analysis of LZTS1 ORF, performed in different type of cancers revealed the presence of the somatic point mutations listed hereinafter (Vecchione et al., 2001; Knowles et al., 2005):
- S29P: (TCC->CCC) reported in a primary esophageal tumor
- K119E: (AAG->GAG) reported in a primary esophageal tumor
- Q501Stop: (CAG->TAG) reported in PC3 (prostate cancer cell line)
- H17R: (CAC->CGC) reported in a diffuse-type gastric carcinoma
- L113P: (CTA->CCA) reported in a bladder tumor sample
- G374S: (GGC->AGC) reported in A1698 (bladder cancer cell line)
- L475V: (CTG->GTG) reported in SCaBER (bladder cancer cell line).

Internally truncated transcripts described in different cancers (Ishii et al., 1999):
- Frameshift deletion 1546-1542 (exons affected: 1,2,3) reported in esophagus cancer
- In-frame deletion 558-1715 (exons affected: 2,3) reported in esophagus cancer
- In-frame deletion 1366-1641 (exon affected: 3) reported in prostate cancer
- In-frame deletion 1402-1578 (exon affected: 3) reported in esophagus and prostate cancer and in acute lymphoblastic leukemia
- In-frame deletion 1417-1515 (exon affected: 3) reported in melanoma
- In-frame deletion 1516-1584 (exon affected: 3) reported in melanoma.

A detailed DNA sequence analysis of LZTS1 gene performed in germline DNA extracted from a screening panel of sporadic and hereditary prostate cancers revealed the presence of 24 SNP. The four SNP listed below have a statistically significant association with sporadic prostate cancer (Hawkins et al., 2002):
- A allele of WF101-010 (2812G → A)
- C allele of WF101-012 (2883T → C)
- C allele of WF101-031 (3329C → T)
- G allele of WF101-014 (4361C → T).

Implicated in

Entity name
Prostate cancer
The DNA sequence analysis of LZTS1 performed on sporadic and hereditary prostate cancer (HPC) samples and unaffected controls revealed the presence of several SNPs associated with prostate cancer (Hawkins et al., 2002). Over-expression of LZTS1 cDNA modulates colony-forming efficiency and proliferation in different prostate cancer cell lines (Cabeza-Arvelaiz et al., 2001).
Entity name
Ovarian cancer
An immunohistochemical analysis of LZTS1 protein expression performed in ovarian carcinomas tissue samples demonstrated that cytoplasmic staining for FEZ1 protein was absent or drastically reduced in 38% of cases (Califano et al., 2010). In addition, homozygous deletions at LZTS1 locus has been detected in advanced ovarian clear cell carcinomas (Kuo et al., 2010).
Entity name
Oral squamous cell carcinoma
Reduced LZTS1 gene expression has been reported in 35% of oral squamous cell carcinoma (SSC) samples and in oral SSC-derived cell lines (Ono et al., 2003).
Entity name
Uveal melanoma
A gene expression profiling performed on 53 primary uveal melanomas by array-based comparative genomic hybridization demonstrated that LZTS1 expression was reduced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and non metastasizing uveal melanomas.
Moreover overexpression of LZTS1 in metastasizing uveal melanoma-derived cells inhibited their motility and invasion (Onken et al., 2008).
Entity name
Lung carcinoma
The immunohistochemical analysis of LZTS1 expression in 103 primary lung cancer specimens demonstrated absence or strong reduction in respectively in more that 42% of cases. A positive correlation between loss of LZTS1 and tumor grading, and between strong LZTS1 expression and mortality rate reduction was also observed (Nonaka et al., 2005). Moreover reduced LZTS1 expression was also detected in several lung cancer derived cell lines (Toyooka et al., 2002).
Entity name
Gastric carcinoma
The immunohistochemical analysis of LZTS1 expression, performed in 88 gastric cancer specimens demonstrated that it is lost or significantly reduced in more than 44% of cases. In addition, DNA allelotyping analysis at the LZTS1 locus showed LOH and microsatellite instability respectively in 18% and 23,5% of cases (Vecchione et al., 2001).
Entity name
Breast carcinoma
LZTS1 gene expression was reduced in breast primary tumors and breast cancer cell lines. The immunohistochemical analysis of LZTS1 expression demonstrated that LZTS1 was absent or down-regulated in primary breast carcinomas compared with normal breast. Moreover, reduced LZTS1 expression was significantly correlated with high histologic grade, lymph node metastasis, and poor prognosis. In addition, DNA methylation analysis demonstrated that LZTS1 loss of expression in breast tumors is correlated with gene methylation. Moreover, overexpression of LZTS1 in breast cancer cell lines inhibits cell proliferation, migration and invasion, and induces morphological and molecular changes characteristic of mesenchymal-to-epithelial transition (Chen et al., 2009; Wang et al., 2011).
Entity name
Bladder cancer
LZTS1 protein expression is reduced in bladder tumor samples and bladder cancer derived cell lines. Reintroduction of LZTS1 expression in TCC derived cell line inhibited cell growth, altered cell cycle progression and suppressed subcutaneous tumor growth in nude mice. Several LZTS1 somatic point mutations have also been reported in bladder cancers tissues and cell lines (Vecchione et al., 2002; Knowles et al., 2005). Moreover, it has been demonstrated by treating heterozygous and nullizygous Lzts1 mice with a classical bladder carcinogen (N-butyl-N-(4-hydroxybutil) nitrosamine, BBN), that the loss of one or both Lzts1 alleles favored development of bladder cancer. These results demonstrated that LZTS1 could represent an important therapeutic target for bladder tumor treatment.


Pubmed IDLast YearTitleAuthors
181926902008Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis.Baffa R et al
178735192007Take your "M" time.Baldassarre G et al
180293482008Toward a confocal subcellular atlas of the human proteome.Barbe L et al
114642832001Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22.Cabeza-Arvelaiz Y et al
198858412010FEZ1/LZTS1 protein expression in ovarian cancer.Califano D et al
186860282009Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis.Chen L et al
123774062002Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.Hawkins GA et al
100971401999The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors.Ishii H et al
115049212001FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis.Ishii H et al
159228642005Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer.Knowles MA et al
202338892010DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma.Kuo KT et al
157350042005Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer.Nonaka D et al
185595912008A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.Onken MD et al
128516772003Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas.Ono K et al
121144332002Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures.Toyooka S et al
177189122007Fez1/Lzts1 a new mitotic regulator implicated in cancer development.Vecchione A et al
214194752011Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma.Wang XX et al

Other Information

Locus ID:

NCBI: 11178
MIM: 606551
HGNC: 13861
Ensembl: ENSG00000061337


dbSNP: 11178
ClinVar: 11178
TCGA: ENSG00000061337


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
236956712013MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1.107
200832282010Genome-wide analysis of chromosomal alterations in patients with esophageal squamous cell carcinoma exposed to tobacco and betel quid from high-risk area in India.27
185595912008A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.26
193392702009Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project.24
248024072014miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1.18
186860282009Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis.13
214194752011Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma.12
128516772003Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas.10
244484682014LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer.10
256671212015The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway.8


Andrea Vecchione ; Luca Lavra ; Carlo M Croce

LZTS1 (leucine zipper, putative tumor suppressor 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-06-01

Online version: http://atlasgeneticsoncology.org/gene/367/lzts1-(leucine-zipper-putative-tumor-suppressor-1)